MICA: New combination therapy against MDR TB targeting the respiratory chain

结核病是与抗菌素耐药性有关的主要死亡原因。2016年，全球估计有1040万例结核病新发病例，170万例结核病相关死亡。耐多药结核病正在上升，在全球范围内，耐多药结核病的平均治愈率仅为54%，广泛耐药结核病的平均治愈率仅为30%。结核病是一种贫困疾病，目前，95%的结核病相关死亡发生在中低收入国家。拟议的活动主要和直接与低收入和中等收入国家的健康需求相关，因此符合官方发展援助要求。迫切需要能够克服当前耐药机制的新型联合疗法。在这里，我们希望验证一种针对结核分枝杆菌（结核的致病病原体）的多种呼吸链组分的令人兴奋的新治疗方法。来自学术界和制药行业的共同研究人员具有独特的优势，可以利用这一策略，他们拥有(i)广泛的领域专业知识，（ii）包含4种关键呼吸链成分选择性抑制剂的专有化合物库，（iii）获得有效的体外和体内模型，用于评估药物组合的疗效，以及（iv）抑制剂和组合方法的背景知识产权（IP）。我们的目标是使用金标准的体外和体内结核病疾病模型来验证这种方法，并确定最可能在临床中具有价值的最佳抗结核效果的靶标组合。此外，我们还将研究抑制剂组合的潜力，以减少新的耐药性的出现，从而可能延长任何新的治疗溶液的寿命。由此产生的信息将为药物发现和开发计划提供信息和帮助，这些计划旨在确定呼吸链成分的抑制剂，当这些抑制剂一起使用时，应该有助于耐多药结核病的新药物方案的灭菌活性，从而缩短患者的治疗时间。将直接受益于研究成果的正在进行的发现项目包括我们自己和我们的工业合作伙伴；此外，我们希望所产生的数据能够激励更广泛的结核病社区开展更多的结核病发现和开发项目。

Tuberculosis (TB) is the main cause of deaths related to antimicrobial resistance. In 2016, there were an estimated 10.4 million new TB cases worldwide, and 1.7 million TB-associated deaths. Multi -drug-resistant (MDR) TB is on the rise and globally, the average cure rate for MDR-TB is only 54% and only 30% for extensively drug resistant TB (XDR-TB). TB is a disease of poverty and presently, 95 % of the TB-related deaths occur in LMICs. The proposed activities are primarily and directly relevant to the health needs of LMIC and therefore ODA compliantNew combination therapies that can overcome current resistance mechanisms are urgently required. Here, we wish to validate an exciting new therapeutic approach of targeting multiple respiratory chain components of Mycobacterium tuberculosis, the causative pathogen of TB. The co-investigators, assembled from both academia and the pharmaceutical industry, are uniquely placed to exploit this strategy possessing (i) extensive domain expertise, (ii) proprietary compound libraries containing selective inhibitors of 4 key respiratory chain components, (iii) access to validated in vitro and in vivo models for assessment of efficacy for drug combinations and (iv) background intellectual property (IP) to both inhibitors and the combinatorial approach. Our objective is to gain validation of this approach using gold-standard in vitro and vivo disease models of TB and to identify the combination of targets eliciting the optimal antitubercular effect which are most likely to be of value in the clinic. In addition, we will also investigate the potential of inhibitor combinations, in reducing the emergence of new drug resistance, thus potentially extending the lifetime of any new therapeutic solution.The resulting information will inform and aid in prioritization of drug discovery and development programs that aim to identify inhibitors of respiratory chain components that, when used together, should contribute sterilizing activity to novel drug regimens for MDR-TB, resulting in shorter treatment times for patients. Ongoing discovery programs that will directly benefit from the research output include our own and those of our industrial partner; in addition, we expect the data generated to inspire additional TB discovery and development programs in the wider TB community.